Anthelmintic quaternaryalkyl acylhydrazones, method of use and compositions

ABSTRACT

This invention concerns a process for killing internal parasites, especially nematodes, trematodes and cestodes affecting warm blooded animals such as sheep, cattle, swine, goats, dogs, cats, horses and humans as well as poultry by administering an effective amount of a compound of the Formula I. ##STR1## The compounds are readily prepared by conventional chemical reactions.

CROSS-REFERENCE

This is a continuation-in-part of U.S. patent application Ser. No.06/849,039, filed Apr. 7, 1986, now abandoned.

SUMMARY OF THE INVENTION

This invention pertains to a new method for killing and controllingworms (Helminths), and new formulations for killing and controllingworms in animals and new chemical compounds The invention is moreparticularly directed to a new method for killing and controllingparasitic worms in animals with certain quaternaryalkyl acylhydrazonesto new anthelmintic formulations comprising the same, and to newquaternaryalkyl acylhydrazones.

The anthelmintic quaternaryalkyl acylhydrazones have the generalstructural formula I.

BACKGROUND OF THE INVENTION

The diseases or groups of diseases described generally as helminthiasisare due to infection of the animal with parasitic worms known ashelminths. Helminthiasis and helminthosis are prevalent and may lead toserious economic problems in valuable warm-blooded domestic animals suchas sheep, swine, cattle, goats, dogs, cats, horses poultry and man.Among the helminths, the groups of worms known as nematodes trematodesand cestodes cause widespread and often-times serious infections invarious species of animals including man. The most common genera ofnematodes, trematodes and cestodes infecting the animals referred toabove are Dityocaulus, Haemonchus, Trichostrongylus, Ostertagia,Nematodirus, Cooperia, Bunostomum, Oesouhagostomum, Chabertia,Strongyloides, Trichuris, Fasciola, Dicrocoelium, Enterobius, Ascaris,Toxascaris, Toxocara, Ascaridia, Capillaria, Heterakis, Ancylostoma,Uncinaria, Dirofilaria, Onchocerca, Taenia, Moniezia, Dipylidium,Metastrongylus, Triodontophorus, Macracanthorhynchus, Hyostroncylus, andStrongylus. Some of these genera attack primarily the intestinal tractwhile others, inhabit the stomach, lungs, liver and subcutaneoustissues. The parasitic infections causing helminthiasis and helminthosislead to anemia, malnutrition, weakness, weight loss, unthriftiness,severe damage to the gastrointestinal tract wall and, if left to runtheir course, may result in death of the infected animals.

The anthelmintic activity of quaternaryalkyl acylhydrazones has not beenpreviously reported.

DETAILED DESCRIPTION OF THE INVENTION

The quaternaryalkyl acylhydrazones of the invention, including hydratesthereof or pharmaceutically acceptable salts thereof, are represented byFormula I wherein W is selected from the group consisting of

(1) pyridinyl or pyridinyl N-oxide (A);

(2) quinolinyl or quinolinyl N-oxide (B);

(3) thienyl (D₁);

(4) furanyl (D₂);

(5) pyrrolyl (D₃);

(6) 1-methylpyrrolyl (D₄);

(7) 1-phenylpyrrolyl (D₅);

(8) 1-benzylpyrrolyl (D₆);

(9) benzofuranyl (E₁);

(10) benzothienyl (E₂);

(11) indolyl (E₃);

(12) 1-methylindolyl (E₄);

(13) 1-phenylindolyl (E₅); or

(14) 1-benzylindolyl (E₆);

(15) thiazolyl (F);

(16) pyrazolyl (G):

(17) pyrazinyl (H);

(18) 1,2,3-triazolyl (I);

wherein the variable substituents (1)-(18) are optionally substitutedwith one or two C₁ -C₄ alkyl, preferably C₁ -C₃ alkyl; C₁ -C₃ alkoxy; C₁-C₃ alkylthio; halo; trifluoromethyl; or hydroxy; with the proviso thatonly one substituent is hydroxy;

wherein R₁ is hydrogen; C₁ -C₄ alkyl; cyclo(C₃ -C₆)alkyl optionallysubstituted with one, 2 or 3 C₁ -C₃ alkyl, preferably cyclo(C₃ -C₅)alkyloptionally substituted; phenyl optionally substituted with one, 2 or 3C₁ -C₄ alkyl, halo, trifluoromethyl, or C₁ -C₃ alkoxy; phenyl(C₁-C₃)alkyl optionally substituted with one, 2 or 3 C₁ -C₄ alkyl, halo,trifluoromethyl, or C₁ -C₃ alkoxy; or 1,3-dioxacyclohexan-5-yl;

wherein n is 1-4; wherein:

(a) R₂, R₃, R₄, being the same or different, are hydrogen., C₁ -C₄alkyl; phenyl optionally substituted with one, 2 or 3 C₁ -C₄ alkyl or C₁-C₃ alkoxy; phenyl(C₁ -C₃)alkyl; or

(b) two of R₂, R₃ and R₄ are taken together with the nitrogen to form afour to seven-member saturated or partially unsaturatednitrogen-containing ring optionally substituted with phenyl and/or oneor two C₁ -C₄ alkyl or C₁ -C₄ alkoxy, said ring optionally containing anoxygen or sulfur atom as a ring member, and the third of R₂, R₃ and R₄is hydrogen; C₁ -C₄ alkyl; phenyl optionally substituted with one, 2 or3 C₁ -C₄ alkyl or C₁ -C₃ alkoxy; or phenyl(C₁ -C₃)alkyl; or

(c) R₂, R₃, and R₄ are taken together with the nitrogen to form a 6 or 7member nitrogen-containing aromatic ring optionally substituted withphenyl and/or one or 2 C₁ -C₄ alkyl or C₁ -C₃ alkoxy; or

(d) two of R₂, R₃ and R₄ are taken together with the nitrogen to form aneight to ten-member saturated or partially unsaturatednitrogen-containing bicylic ring optionally substituted with phenyland/or one or two C₁ -C₄ alkyl or C₁ -C₄ alkoxy, said ring optionallycontaining an oxygen or sulfur atom as a ring member, and the third ofR₂, R₃ and R₄ is hydrogen; C₁ -C₄ alkyl; phenyl optionally substitutedwith one, 2 or 3 C₁ -C₄ alkyl or C₁ -C₃ alkoxy; or phenyl(C₁ -C₃)alkyl;or

(e) R₂, R₃, and R₄ are taken together with the nitrogen to form an eightto ten member nitrogen-containing aromatic bicyclic ring optionallysubstituted with phenyl and/or one or 2 C₁ -C₄ alkyl or C₁ -C₃ alkoxy;and

X is an anion.

Examples of anions are halides, preferably chloride or bromide, acetate,or benzenesulfonate.

Examples of the moiety (-N⁺ -R₂,R₃,R₄) include ammonium, methylammonium,diethylammonium, methyldiphenylammonium, bisphenylmethylammonium,methyl(phenylmethyl)ammonium, methyl(2-phenylethyl)ammonium,1-methylpiperidinium, 1-ethylmorpholinium,1-methyl-4-phenyl-1H,2,5,6-tetrahydropyridinium, 2-methoxypyridinium,4-methylpyridinium, quinolinium, isoquinolinium,4-methoxy-1-methylindolium, 1-azabicyclo[2,2,2]octanium,1-methyl-1-azacycloheptatrienium, 2,5-dihydro-1-methylpyrrolidinum, and1-ethylazetidinium.

C₋₋ -C₋₋ means the carbon content of various hydrocarbon-containingmoieties is indicated by a prefix designating the minimum and maximumnumber of carbon atoms in the moiety. Thus (C₁ -C₃) alkyl refers toalkyl of one to 3 carbon atoms, inclusive or methyl, ethyl, propyl, andisopropyl.

Halogen atom (halo) refers to a bromo, chloro, iodo or fluoro atom.

Pharmaceutically acceptable refers to those properties and/or substanceswhich are acceptable to the patient from apharmacologically-toxicological point of view and to the manufacturingpharmaceutical chemist from a physical-chemical point of view regardingcomposition, formulation, stability, patient acceptance andbioavailability.

Examples of C₁ -C₄ alkyl are methyl, ethyl, propyl, butyl and isomericforms thereof. Examples of C₁ -C₃ alkoxy are methoxy, ethoxy, propoxyand isomeric forms thereof.

Examples of phenyl(C₁ -C₃)alkyl are benzyl, phenylethyl andphenylpropyl. Examples of phenyl(C₁ -C₃)alkyl substituted with one, 2 or3 C₁ -C₄ alkoxy, halo or trifluoromethyl include 4-chlorobenzyl,2-chlorophenylethyl, p-tolylethyl, 2-methylbenzyl, 4-methoxybenzyl.Examples of C₁ -C₃ alkylthio include methylthio, ethylthio, andn-propylthio.

Preferred quaternaryalkyl acylhydrazones of Formula I are where W ispyridinyl, i.e. a pyridinyl quaternaryalkyl acylhydrazones (IA).

Preferred R₁ include hydrogen, methyl or benzyl;

Preferred n is one;

Preferred R₂, R₃ and R₄ include methyl or the case when R₂, R₃ and R₄are taken together with the nitrogen to form pyridine;

Preferred X is chloride.

One embodiment of this invention includes, of course, the anthelminticuse and anthelmintic compositions of compounds of Formula I, hydratesthereof or pharmaceutically acceptable salts thereof.

One embodiment of this invention includes, of course, the anti-filariause and anti-filaria compositions of compounds of Formula I, hydratesthereof or pharmaceutically acceptable salts thereof.

Still another embodiment of this invention are the novel compounds,hydrates thereof or pharmaceutically acceptable salts thereof accordingto Formula I, IA, IB, ID (including ID₁, ID₂, ID₃, ID₄, ID₅, ID₆), IE(including IE₁, IE₂, IE₃, IE₄, IE₅, IE₆, IF, IG, IH and II).

wherein W, R₁, R₂, R₃, R₄, X are described above;

wherein Y and Z, being the same or different, are hydrogen, hydroxy, C₁-C₄ alkyl, C₁ -C₃ alkoxy, C₁ -C₃ alkylthio, halo, or trifluoromethyl;

G is an oxygen atom, a sulfur atom or a N-V group;

V is hydrogen; C₁ -C₃ alkyl, preferably methyl, phenyl, phenyl-(C₁-C₃)alkyl, preferably benzyl; and

m is 0 or 1.

A is pyridinyl (or pyridinyl N-oxide) optionally substituted with one ortwo C₁ -C₄ alkyl, C₁ -C₃ alkoxy, C₁ -C₃ alkylthio, halo,trifluoromethyl, or hydroxy;

B is quinolinyl (or quinolinyl N-oxide) optionally substituted with oneor two C₁ -C₄ alkyl, C₁ -C₃ alkoxy, C₁ -C₃ alkylthio, halo,trifluoromethyl, or hydroxy;

D₁ is thienyl optionally substituted with one or two C₁ -C₃ alkyl, C₁-C₃ alkoxy, C₁ -C₃ alkylthio, halo, trifluoromethyl, or hydroxy; when Gis a sulfur atom;

D₂ is furanyl optionally substituted with one or two C₁ -C₄ alkyl, C₁-C₃ alkoxy, C₁ -C₃ alkylthio, halo, trifluoromethyl, or hydroxy; when Gis an oxygen atom;

D₃ is pyrrolyl optionally substituted with one or two C₁ -C₄ alkyl, C₁-C₃ alkoxy, C₁ -C₃ alkylthio, halo, trifluoromethyl, or hydroxy; when Gis N-V and V is hydrogen;

D₄ is 1-methylpyrrolyl optionally substituted with one or two C₁ -C₄alkyl, C₁ -C₃ alkoxy, C₁ -C₃ alkylthio, halo, trifluoromethyl, orhydroxy; when G is N-V and V is methyl;

D₅ is 1-phenylpyrrolyl optionally substituted with one or two C₁ -C₄alkyl, C₁ -C₃ alkoxy, C₁ -C₃ alkylthio, halo, trifluoromethyl, orhydroxy; when G is N-V and V is phenyl;

D₆ is 1-benzylpyrrolyl optionally substituted with one or two C₁ -C₄alkyl, C₁ -C₃ alkoxy, C₁ -C₃ alkylthio, halo, trifluoromethyl, orhydroxy; when G is N-V and V is benzyl;

E₁ is benzofuranyl optionally substituted with one or two C₁ -C₄ alkyl,C₁ -C₃ alkoxy, C₁ -C₃ alkylthio, halo, trifluoromethyl, or hydroxy; whenG is an oxygen atom;

E₂ is benzothienyl optionally substituted with one or two C₁ -C₄ alkyl,C₁ -C₃ alkoxy, C₁ -C₃ alkylthio, halo, trifluoromethyl, or hydroxy; whenG is a sulfur atom;

E₃ is indolyl optionally substituted with one or two C₁ -C₄ alkyl, C₁-C₃ alkoxy, C₁ -C₃ alkylthio, halo, trifluoromethyl, or hydroxy; when Gis N-V and V is hydrogen;

E₄ is 1-methylindolyl optionally substituted with one or two C₁ -C₄alkyl, C₁ -C₃ alkoxy, C₁ -C₃ alkylthio, halo, trifluoromethyl, orhydroxy; when G is N-V and V is methyl;

E₅ is 1-phenylindolyl optionally substituted with one or two C₁ -C₄alkyl, C₁ -C₃ alkoxy, C₁ -C₃ alkylthio, halo, trifluoromethyl, orhydroxy; when G is N-V and V is phenyl; or

E₆ is 1-benzylinodyl optionally substituted with one or two C₁ -C₄alkyl, C₁ -C₃ alkoxy, C₁ -C₃ alkylthio, halo, trifluoromethyl, orhydroxy; when G is N-V and V is benzyl;

F is thiazolyl optionally substituted with one or two C₁ -C₄ alkyl, C₁-C₃ alkoxy, C₁ -C₃ alkylthio, halo, trifluoromethyl, or hydroxy;

G is pyrazolyl optionally substituted with one or two C₁ -C₄ alkyl, C₁-C₃ alkoxy, C₁ -C₃ alkylthio, halo, trifluoromethyl, or hydroxy;

H is pyrazinyl optionally substituted with one or two C₁ -C₄ alkyl, C₁-C₃ alkoxy, C₁ -C₃ alkylthio, halo, trifluoromethyl, or hydroxy;

I is triazolyl optionally substituted with one or two C₁ -C₄ alkyl, C₁-C₃ alkoxy, C₁ -C₃ alkylthio, halo, trifluoromethyl, or hydroxy;

with the overall proviso that only one substituent is hydroxy.

Among the quaternaryalkyl acylhydrazones of Formula I:

1-[[[1-(3-pyridinyl)ethylidene]hydrazino]carbonyl]methyl]-pyridiniumchloride (Cpd #2);

1-[[[1-(3-pyridinyl)ethylidene]hydrazino]carbonyl]propyl]-pyridiniumchloride;

Trimethyl [[3-(4-pyridinylmethylene)carbazoyl]methyl]ammonium chloride(Cpd #6, CA RN 6958-26-5);

(carboxymethyl)trimethylammonium chloride, furfurylidenehydrazide (CA RN6958-15-2);

(carboxymethyl)trimethylammonium chloride, 2-thienylidenehydrazide (CARN 6958-28-7);

(Carboxymethyl)trimethylammonium chloride,2-(pyrrol-2-yl-methylene)hydrazide (Cpd #61, CA 93786-81-3)

are known. See T. Kirchenmayer and F. Kuffner, Monatsh. Chem. 93,1237-41 (1962); Chem. Abstr. 58:9613C; CAS ON LINE Search (1967 todate); H. Tanaka and O. Yamuchi, Chem. Pharm. Bull (Tokyo) 10, 435-9(1962); Chem. Abstr. 58, 4498d.

Other known quaternaryalkyl acylhydrazones include(carboxymethyl)trimethylammonium chloride,5-cyanobenzofurfurylidenehydrazide (CA RN 84223-53-0) and(carboxymethyl)trimethylammonium chloride,2-[2-[[3-(2-ethoxy-2-oxoethyl)-4-(3-ethoxy-3-oxo-propyl)-1H-pyrrol-2-yl-hydrazide(CA RN 38256-20-1).

The quaternaryalkyl acylhydrazones of the invention (Formula I) arereadily prepared by reacting the appropriate heteroaromatic carbonylcompound (ketone or aldehyde) II with the acylhydrazone (known as aGirard Reagent) III (Chart A, Scheme A) or by heating the heteroaromaticcarbonyl compound II with hydrazine IV to form the hydrazoneintermediate (V) which is then acylated with the halide or anhydride(VI) to form the acylhydrazone (I) (Chart A, Scheme B).

A third route the quaternaryalkyl acylhydrazone (I) is to react theheteroaromatic carbonyl compound II with the acylhydrazide VII to forman intermediate acylhydrazone VIII which is in the final stage reactedwith the amine IX to yield I (Chart A, Scheme C).

The condensation reactions of Schemes A, C, and B are carried out in thepresence of a suitable solvent; for example, alcohols, ethers,halogenated hydrocarbons, hydrocarbons and include methanol, ethanol,isopropanol, propanol, hexane, tetrahydrofuran, dioxane, and preferablyethanol.

The acylation reaction of Scheme B is carried out in the presence of anonprotolytic solvent such as ether, halogenated hydrocarbons,hydrocarbons and includes hexane, tetrahydrofuran, dioxane, methylenechloride and preferably methylene chloride.

The starting heteroaromatic ketone and aldehyde intermediates arecommercially available or prepared by known methods such as R. C. Frankand C. Weatherbee, J. Am. Chem. Soc., 70, 3482-3 (1948); D. Milstein andJ. K. Stille, J. Org. Chem., 44, 1613-1618 (1979); J. E. Parko, B. E.Wagner and R. H. Holm, J. Organometallic Chem., 56, 53 (1963); E. B.Sanders, H. V. Secor and J. I. Seeman, J. Org. Chem., 43, 324-330(1978).

The hydrazides III and VII are commercially available or readilysynthesized by known procedures such as N B. Maheshi et al., J. IndianChem. Soc., 42, 67-74 (1965).

The following detailed examples procedures describe how to preparevarious quaternaryalkyl acylhydrazones of the invention and are to beconstrued as merely illustrative and not limitations of the precedingdisclosure in any way whatsoever. Those skilled in the art will promptlyrecognize appropriate variations from the procedures both as toreactants as well as to reaction conditions and techniques.

EXAMPLE 11-[2-oxo-2-[[2-phenyl-1-(2-pyridinyl)ethylidene]-hydrazino]ethyl]pyridiniumchloride. Compound 1

To 5.3 gm (0.03 mole) of Girard Reagent P in 50 ml of methanol is added5.92 gm (0.03 mole) of benzyl 2-pyridinyl ketone. The mixture isrefluxed 2.5 hr. The solvent is evaporated giving a black residue. Theresidue is slurried in anhydrous ether and the solids collected. Thecrude solid is crystallized (decolorized with carbon) and thenrecrystallized twice from ethanol to give 3.55 gm (32%) of the titlecompound; mp 240.5° (decomp).

Calcd: C, 65.48; H, 5.18; N, 15.28.

Found: C, 64.78; H, 5.26; N, 15.14.

EXAMPLE 21-[[[[1-(3-pyridinyl)ethylidene]hydrazino]carbonyl]-methyl]pyridiniumchloride. Compound 2

To 5.63 gm (0.03 mole) of Girard's Reagent P in 50 ml of anhydrousmethanol is added 3.63 gm (0.03 mole) of 3-acetylpyridine. The solutionis refluxed 3 hr and cooled. The solvent is evaporated The residue isslurried in 100 ml of anhydrous ether and filtered. The crude product isrecrystallized from absolute ethanol to afford 6.18 gm (71%) of thetitle compound; mp 237.2° (decomp).

Calcd: C, 57.83; H, 5.16; N, 19.28.

Found: C, 57.64; H, 5.13; N, 19.36.

EXAMPLE 31-[[[[1-(2-pyridinyl)ethylidene]hydrazino]carbonyl]methyl]pyridiniumchloride. Compound 3

Following the general method of Example 2 and making non-criticalvariations, 5.63 gm (0.03 mole) of Girard's Reagent P and 3.63 gm (0.03mole) of 2-acetylpyridine yield 5.70 gm (65%) of the title compound; mp183.7° (decomp).

Calcd: C, 57.83; H, 5.16; N, 19.28; Cl, 12.20.

Found: C, 58.27; H, 5.44; N, 19.08.

1-[[[[1-(2-pyridinyl)ethylidene]hydrazinocarbonyl]methyl]-pyridiniumchloride is remade, with a scape-up of 7.5x, using the above procedureto give 17.5 gm (26%) in three crops.

Found: C, 54.61; H, 4.99; N, 18.29; Cl, 12.09; mp 143°-144°.

Found: C, 53.99; H, 5.22; N, 17.32; Cl, 10.71; mp 142°-143°. C, 55 27;H, 5.09; N, 19.18; Cl, 11.33; mp 141°-143°.

EXAMPLE 4 Trimethyl [[3-[1-(3-pyridinyl)ethylidene]carbazoyl]-ammoniumchloride monohydrate. Compound 4

To 5.3 gm (0.03 mole) of Girard's Reagent T in 100 ml methanol is added3.63 gm (0.03 mole) of 3-acetylpyridine. The reaction mixture isrefluxed 6 hr and cooled to give crystals. The product is collected andrecrystallized from methanol to afford 6.08 gm (70%) of the titlecompound; mp 199.4° (decomp)

Calcd: C, 49.91; H, 7.28; N, 19.41.

Found: C, 50.24; H, 7.23; N, 19.63.

EXAMPLE 5 Trimethyl[[3-[1-(4-pyridinyl)ethylidene]carbazoyl]methyl]ammonium chloride.Compound 5

Following the general method of Example 4 and making non-criticalvariations, 5.03 gm (0.03 mole) of Girard's Reagent T and 3.63 gm (0.03mole) of 4-acetylpyridine yield 3.76 gm (45%) of the title compound; mp213° (decomp).

Calcd: C, 51.19; H, 7.18; N, 19.91.

Found: C, 50.92; H, 7.05; N, 19.73.

EXAMPLE 6 Trimethyl [[3-(4-pyridinylmethylene)carbazoyl]methyl]-ammoniumchloride. Compound 6

Following the general method of Example 4 and making non-criticalvariations, 5 03 gm (0.03 mole) of Girard's Reagent T and gm (0.03 mole)of 4-pyridinecarboxaldehyde yield 4.35 gm (56%) of the title compound;mp 220° (decomp).

Calcd: C, 51.46; H, 6.63; N, 21.83.

Found: C, 51.85; H, 6.90; N, 21.94.

EXAMPLE 7 Trimethyl [[3-[1-(2pyridinyl)ethylidene]carbazoyl]-methyl]ammonium chloride. Compound 7.

Following the general method of Example 4 and making non-criticalvariations, 5.03 gm (0.03 mole) of Girard's Reagent T and 3.63 gm (0.03mole) of 2-acetylpyridine yield 2.05 gm (24%) of the title compound; mp208.2° (decomp).

Calcd: C, 49.91; H, 7.28; N, 19.41.

Found: C, 50.34; H, 7.49; N, 19.54.

Employing the above procedure, using a 5.2x scale-up gives 25.74 gm(58%) of the title compound, mp 190.0°.

EXAMPLE 8 Dimethyl[[3-(2-thienylmethylene)carbazoyl]methyl]-ammoniumchloride. (Compound 18)

A mixture of 7.68 gm (0.05 mole) Girard Reagent D, 5.61 gm (0.05 mole)2-thiophenecarboxyaldehyde, 3 drops of concentrated hydrochloric acidand 250 ml of absolute ethanol is refluxed 12 hr. The solvent isevaporated. The residue is dissolved in absolute ethanol, treated withDarco decolorizing carbon and filtered. The filtrate is chilled. Thesolid which deposits is collected, washed with ether and dried to give8.1 gm (65%) of the title compound having a melting point of 207.9° C.with decomposition.

Calcd: C, 43.63; lf, 5.70; N, 16.96.

Found: C, 51.85; lf, 5.72; N, 17.08.

The compounds prepared according to Examples 1-8 are tabulated in TableA along with other illustrative compounds of the invention preparedfollowing the general procedure/example indicated (1-8) and makingnon-critical variations, except starting with the appropriate ketone(II) and aryl hydrazide/carbazate (III).

The quaternaryalkyl acylhydrazones of this invention are effectiveagainst worms, particularly parasitic worms of valuable domesticwarm-blooded animals including helminth parasites in ovines (sheep) andbovines (cattle) but more particularly the filarial parasites ofwarm-blooded animals including dogs and man.

Although non of the pyridinyl quarternaryalkyl acylhydrazones of thisinvention tested have demonstrated significant activity againstNematospiroides dubius in mice, observations in sheep experimentallyinfected with Haemonchus contortus in accordance with Procedure I,generally confirm anthelmintic activity upon oral administration as setforth in Table I. Quaternaryalkyl acylhydrazones which are toxic areexpected to exhibit anthelmintic activity at a lower non-toxic dose.

Further observations in male Mongolian jirds infected with Brugiapahangi and Dipetalonema viteae (Procedure II) confirm macro- andmicrofilaricidal activity of an quaternaryalkyl acylhydrazone of thisinvention (Table II).

PROCEDURE NO. I

In individual experiments all sheep are treated identically, howevernon-critical variations occur between experiments All of the sheep usedin this procedure are treated twice with levamisole hydrochloride orallyat 8 mg/kg or once each with ivermectin parenterally at 200 μg/kg andlevamisole hydrochloride orally at 8 mg/kg. The second treatment in eachcase is administered 4-7 days after the first treatment. Two weeks afterthe second treatment all sheep are inoculated per os with ˜3,500 to˜7,500 infective larvae of H. contortus. Rectal fecal samples are takenfrom each sheep 26-41 days post-inoculation (PI). and these samples areexamined for eggs of H. contortus using the McMaster counting chambertechnique. All sheep harboring good infections of H. contortus arerandomly allocated to a treatment group; those which do not exhibitsuitable infections are dropped from the study. One-three days later ondays 27-42 PI each sheep remaining in the study (excluding thenontreated controls) is treated with a test compound (orally at 100mg/kg unless indicated otherwise) or a standard (levamisolehydrochloride orally at 8 mg/kg) or is used as an untreated control. Allsheep received food and water ad lib throughout the experiment.

Prior to administration, all solid compounds are finely ground using amortar and pestle. Oral compounds are suspended in 20.30 ml of sterilevehicle #98 (each ml contains: carboxymethylcellulose--10 mg,polysorbate 80-84 mg, propylparaben--0.42 mg) using a sonicator andadministered along with a tap water wash via a stomach tube. All testcompounds are given to a single sheep. Two or more sheep are treatedwith levamisole hydrochloride and five are used as nontreated controls.All animals are monitored for signs of toxicity following treatment.

The sheep are sacrificed 7-12 days after treatment (days 35-49 PI), andthe abomasum is ligated and removed from each sheep. Each abomasum islongitudinally sectioned and rinsed into an 80 mesh sieve. Sievecontents are collected in individual containers and fixed informol-alcohol. Later each sample is transferred to a 1000 or 2000 mlbeaker and the volume brought to 400-1000 ml with tap water. The totalnumber of worms in a 40-100 ml aliquot (10%) is determined. When noworms are found in the 10% aliquot, the entire sample is examined. Totalworm number/sheep and percentage clearance for each treatment arecalculated. Percentage clearance for a particular test compound in agiven trial is determined according to the following formula: ##EQU1##

Sheep which die within 24 hr following treatment are not examined forworms, while any that die between 24 hr post-treatment and necropsy areexamined in an identical manner as that described above. The results ofvarious trials are combined and reported in Table I as percentageclearance.

PROCEDURE NO. II Antifilarial Evaluation

Test compound is evaluated for macro- and microfilaricidal activityagainst Brugia pahangi and Dipetalonema viteae in male jirds (Merionerunguiculatus) weighing 50-60 gm. Brugia pahangi is maintained byalternating passage through beagles and Aedes aegypti (selectedLiverpool strain), while D.viteae is cyclically maintained in jirds andthe soft tick, Ornithodoros tartakovsky as described by McCall (C. J.Entomol. 16:283-293, 1981). Prior to the start of the experiment eachjird receives 5 male and 5 female, adult D. viteae by subcutaneoustransplantation. One to 2 weeks later, 10 male and 10 female B. pahangiare transplanted into the peritoneal cavity of each animal (Suswillo andDenham, J. Parasitol. 63:591, 1977). One week later jirds are randomlyallocated to treatment groups (3 animals/treated group and 6animals/nontreated control group). On the following Monday (day 0).pretreatment microfilaremia levels (D. viteae) are determined byspreading a 20 cmm sample of ocular blood over a 20× 15 mm area of aslide in a drop of water. The slide is dried overnight and then stainedwith Giemsa. Microfilariae are counted to a total of at least 200 perslide and the number of fields noted (a minimum of 5 fields must becounted). Since there are 1.43 cmm per 10 fields on the calibratedscope, the number of microfilariae per cmm can be calculated.

On day 0, dosing is also initiated. The compound, suspended inhydroxyethylcellulose (0 5%) and Tween 80 (0.1%). is administered at 100mg/kg/day for 5 days by subcutaneous injection. Microfilaremia levelsare determined on days 4 and 56 posttreatment as described above On˜day60 posttreatment all jirds are sacrificed to determine the effects ofthe drug on adults of D. viteae and B. pahangi in the skin andperitoneal cavity, respectively. Live worms are identified to species,noted as to sex, and counted. The number of dead and/or encapsulatedworms also is recorded. A reduction of ≧80% in microfilaremia or ≧50% inadult worm burden compared to pretreatment microfilaremia or nontreatedcontrol worm burden, respectively, is considered to be significantactivity.

The results for an acylhydrazone of Formula I is set forth in Table II.

DETAILED DESCRIPTION (cont'd)

The quaternaryalkyl acylhydrazones of Formula I can be used as the purecompounds or as mixtures of pure compounds but for practical reasons thecompounds are preferably formulated as anthelmintic compositions andadministered as a single or multiple dose, alone or in combination withother anthelmintics (e.g. avermectins, benzimidazoles, levamisole,praziquantel, etc.). For example, aqueous or oil suspensions can beadministered orally, or the compounds can be formulated with a solidcarrier for feeding. Furthermore, an oil suspension can be convertedinto an aqueous emulsion by mixing with water and injecting the emulsionintra muscularly, subcutaneously or into the peritoneal cavity. Inaddition, the active compound(s) can be administered topically to theanimal in a conventional pour-on formula.

Pure compounds, mixtures of the active compounds, or combinationsthereof with a solid carrier can be administered in the animal's food,or administered in the form of tablets, pills, boluses, wafers, pastes,and other conventional unit dosage forms, as well assustained/controlled release dosage forms which deliver the activecompound over an extended period of days, weeks or months. All of thesevarious forms of the active compounds of this invention can be preparedusing physiologically acceptable carriers and known methods offormulation and manufacture.

Representative solid carriers conveniently available and satisfactoryfor physiologically acceptable, unit dosage formulations include cornstarch, powdered lactose, powdered sucrose, talc, stearic acid,magnesium stearate, finely divided bentonite, and the like. The activeagent can be mixed with a carrier in varying proportions from, forexample, about 0.001 percent by weight in animal feed to about 90 or 95percent or more in a pill or capsule In the latter form, one might useno more carrier than sufficient to bind the particles of activecompound.

In general, the compounds can be formulated in stable powders orgranules for mixing in an amount of feed for a single feeding or enoughfeed for one day and thus obtain therapeutic efficacy withoutcomplication. It is the prepared and stored feeds or feed premixes thatrequire care. A recommended practice is to coat a granular formulationto protect and preserve the active ingredient. A prepared hog-feedcontaining about 0.2 percent of the active compound will provide adosage of about 100 mg per kg body weight for each 100 lb pig in itsdaily ration.

A solid diluent carrier need not be a homogeneous entity, but mixturesof different diluent carriers can include small proportions of adjuvantssuch as water; alcohols; protein solutions and suspensions like skimmedmilk; edible oils; solutions, e.g., syrups; and organic adjuvants suchas propylene glycols, sorbitol, glycerol, diethylcarbonate, and thelike.

The solid carrier formulations of the inventions are convenientlyprepared in unit dosage forms, to facilitate administration to animals.Accordingly, several large boluses (about 20 g weight) amounting toabout 54 g of active compound would be required for a single dosage to a900 lb horse at a dosage rate of 50 mg/kg of body weight. Similarly, a60 lb lamb at a dosage rate of 100 mg/kg of body weight would require apill, capsule, or bolus containing about 2.7 g of active compound. Asmall dog, on the other hand, weighing about 20 lbs. would require atotal dosage of about 225 mg st a dosage rate of 25 mg/kg of bodyweight. The solid, unit dosage forms can be conveniently prepared invarious sizes and concentrations of active ingredient, to accommodatetreatment of the various sizes of animals that are parasitized by worms.

Liquid formulations can also be used. Representative liquid formulationsinclude aqueous (including isotonic saline) suspensions, oil solutionsand suspensions, and oil in water emulsions. Aqueous suspensions areobtained by dispersing the active compound in water preferably includinga suitable surface-active dispersing agent such as cationic anionic, ornon-ionic surface-active agents. Representative suitable ones arepolyoxyalkylene derivatives of fatty alcohols and of sorbitan esters,and glycerol and sorbitan esters of fatty acids. Various dispersing orsuspending agents can be included and representative ones are syntheticand natural gums, tragacanth, acacia, alginate, dextran, gelatin, sodiumcarboxymethylcellulose methylcellulose, sodium polyvinylpyrrolidone, andthe like. The proportion of the active compound in the aqueoussuspensions of the invention can vary from about 1 percent to about 20percent or more.

Oil solutions are prepared by mixing the active compound and an oil,e.g. an edible oil such as cottonseed oil, peanut oil, coconut oil,modified soybean oil, and sesame oil. Usually, solubility in oil will belimited and oil suspensions can be prepared by mixing additional finelydivided compound in the oil.

Oil in water emulsions are prepared by mixing and dispersing an oilsolution or suspension of the active compound in water preferably aidedby surface-active agents and dispersing or suspending agents asindicated above.

In general, the formulations of this invention are administered toanimals so as to achieve therapeutic or prophylactic levels of theactive compound.

In other animals, and for other kinds of parasitic worms, definitivedosages can be proposed. Contemplated are dosage rates of about 1 mg toabout 800 mg/kg of body weight. A preferred, contemplated range ofdosage rates is from about 5 mg to about 400 mg/kg of body weight. Inthis regard, it should be noted that the concentration of activecompound in the formulation selected for administration is in manysituations not critical. One can administer a larger quantity of aformulation having a relatively low concentration and achieve the sametherapeutic or prophylactic dosage as a relatively small quantity of arelatively more concentrated formulation. More frequent small dosageswill likewise give results comparable to one large dose. One can alsoadminister a sustained release dosage system (protracted deliveryformulation) so as to provide therapeutic and/or prophylactic dosageamounts over an extended period Unit dosage forms in accordance withthis invention can have anywhere from less than 1 mg to 500 g of activecompound per unit.

Although the anthelmintic agents of this invention will find theirprimary use in the treatment and/or prevention of helminth parasitisasin domesticated animals such as sheep, cattle, horses, dogs, swine goatsand poultry, they are also effective in treatment that occurs in otherwarm blooded animals including man. The optimum amount to be employedfor best results will, of course, depend upon the particularquaternaryalkyl acylhydrazone compound employed, species of animal to betreated, the regimen treatment and the type and severity of helminthinfection. Generally good results are obtained with compounds of FormulaI by the oral or parenteral route of administration of about 1 to 200mg/kg of animal body weight (such total dose being given at one time, ina protracted manner or in divided doses over a short period of time suchas 1-4 days). The technique for administering these materials to animalsare known to those skilled in the veterinary and medical fields.

It is contemplated that the quaternaryalkyl acylhydrazones of Formula Ican be used in the treatment and/or prevention of Dirofilaria in dogs ata dose of from 1 mg/kg to 100 mg/kg of body weight upon oral and/orparenteral daily/weekly or bimonthly administration depending upon theparticular compound employed and the type and severity of infection.

It is also contemplated that the quaternaryalkyl acylhydrazones ofFormula I can be used to treat various helminth diseases in humans,including those caused by Ascaris, Enterobius, Ancylostoma, Trichuris,Stronzvloides, Fasciola, Taenia, and/or Onchocerca or other filaria at adose of from 1 mg/kg to 300 mg/kg of body weight upon oral and/orparenteral administration.

DEFINITIONS

The definitions and explanations below are for the terms as usedthroughout the entire patent application including both thespecification and claims.

All temperatures are in degrees Celsius.

TLC refers to thin-layer chromatography.

Brine refers to an aqueous saturated sodium chloride solution.

When solvent pairs are used, the ratio of solvents used arevolume/volume (v/v).

                                      TABLE A                                     __________________________________________________________________________     ##STR2##                                 I                                   C W              R.sub.1                                                                           n R.sub.2                                                                          R.sub.3                                                                          R.sub.4                                                                          X.sup.-                                                                          MP, °C.                                                                     P H                                   __________________________________________________________________________     1                                                                              2-pyridinyl    PhCH.sub.2                                                                        1 1-pyridinyl                                                                            Cl 240.5d                                                                             1 -                                    2                                                                              3-pyridinyl    CH.sub.3                                                                          1 1-pyridinyl                                                                            Cl 237.2d                                                                             2 -                                    3                                                                              2-pyridinyl    CH.sub.3                                                                          1 1-pyridinyl                                                                            Cl 183.7d                                                                             2 -                                    4                                                                              3-pyridinyl    CH.sub.3                                                                          1 CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3                                                                         Cl 199.4d                                                                             4 -                                    5                                                                              4-pyridinyl    CH.sub.3                                                                          1 CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3                                                                         Cl 213d 4 -                                    6                                                                              4-pyridinyl    H   1 CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3                                                                         Cl 220d 4 -                                    7                                                                              2-pyridinyl    CH.sub.3                                                                          1 CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3                                                                         Cl 208.2d                                                                             4 -                                    8                                                                               3-thienyl     H   1 1-pyridinyl                                                                            Cl 244.2d                                                                             1 -                                    9                                                                              3-thienyl      H   1 CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3                                                                         Cl 214.6                                                                              1 -                                   10                                                                              3-thienyl      H   1 CH.sub.3                                                                         CH.sub.3                                                                         H  Cl 182.1d                                                                             1 -                                   11                                                                              3-methyl-2-thienyl                                                                           CH.sub.3                                                                          1 1-pyridinyl                                                                            Cl 247.8d                                                                             1 -                                   12                                                                              3-methyl-2-thienyl                                                                           CH.sub.3                                                                          1 CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3                                                                         Cl 209.4d                                                                             1 -                                   13                                                                              2-pyridinyl    CH.sub.3                                                                          1 CH.sub.3                                                                         CH.sub.3                                                                         H  Cl 219.6d                                                                             1 -                                   14                                                                              3-pyridinyl    CH.sub.3                                                                          1 CH.sub.3                                                                         CH.sub.3                                                                         H  Cl 216.1d                                                                             1 -                                   15                                                                              4-pyridinyl    CH.sub.3                                                                          1 CH.sub.3                                                                         CH.sub.3                                                                         H  Cl 180.1                                                                              1 -                                   16                                                                              4-pyridinyl    CH.sub.3                                                                          1 1-pyridinyl                                                                            Cl 272.1d                                                                             1 -                                   17                                                                              2-thienyl      H   1 1-pyridinyl                                                                            Cl 236.1d                                                                             1 -                                   18                                                                              2-thienyl      H   1 CH.sub.3                                                                         CH.sub.3                                                                         H  Cl 207.9d                                                                              8                                                                              -                                   19                                                                              5-chloro-2-thienyl                                                                           CH.sub.3                                                                          1 1-pyridinyl                                                                            Cl 197.6d                                                                             8 -                                   20                                                                              5-chloro-2-thienyl                                                                           CH.sub.3                                                                          1 CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3                                                                         Cl 192.2d                                                                             8 -                                   21                                                                              5-chloro-2-thienyl                                                                           CH.sub.3                                                                          1 CH.sub.3                                                                         CH.sub.3                                                                         H  Cl 183.8                                                                              8 -                                   22                                                                              5-bromo-2-thienyl                                                                            CH.sub.3                                                                          1 1-pyridinyl                                                                            Cl 231.5d                                                                             8 -                                   23                                                                              2,5-dichloro-3-thienyl                                                                       CH.sub.3                                                                          1 1-pyridinyl                                                                            Cl 241.4                                                                              8 -                                   24                                                                              2,5-dichloro-3-thienyl                                                                       CH.sub.3                                                                          1 CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3                                                                         Cl 220.8                                                                              8 -                                   25                                                                              2,5-dimethyl-3-thienyl                                                                       CH.sub.3                                                                          1 1-pyridinyl                                                                            Cl 248.8d                                                                             8 -                                   26                                                                              2,5-dimethyl-3-thienyl                                                                       CH.sub.3                                                                          1 CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3                                                                         Cl 206.7d                                                                             8 -                                   27                                                                              5-methyl-2-thienyl                                                                           CH.sub.3                                                                          1 1-pyridinyl                                                                            Cl 225.7d                                                                             8 -                                   28                                                                              5-methyl-2-thienyl                                                                           CH.sub.3                                                                          1 CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3                                                                         Cl 196.7                                                                              8 -                                   29                                                                              5-methyl-2-thienyl                                                                           CH.sub.3                                                                          1 CH.sub.3                                                                         CH.sub.3                                                                         H  Cl 218.5d                                                                             8 -                                   30                                                                              2-thienyl      CH.sub.3                                                                          1 1-pyridinyl                                                                            Cl 216.3d                                                                             8 -                                   31                                                                              2-thienyl      CH.sub.3                                                                          1 CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3                                                                         Cl 187.8d                                                                             8 -                                   32                                                                              2-thienyl      CH.sub.3                                                                          1 CH.sub.3                                                                         CH.sub.3                                                                         H  Cl 198.2                                                                              8 -                                   33                                                                              3-thienyl      CH.sub.3                                                                          1 1-pyridinyl                                                                            Cl 233.4d                                                                             8 -                                   34                                                                              3-thienyl      CH.sub.3                                                                          1 CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3                                                                         Cl 205.8                                                                              8 -                                   35                                                                              3-thienyl      CH.sub.3                                                                          1 CH.sub.3                                                                         CH.sub.3                                                                         H  Cl 261.2d                                                                             8 -                                   36                                                                              4-methyl-2-thienyl                                                                           CH.sub.3                                                                          1 1-pyridinyl                                                                            Cl 225.2                                                                              8 -                                   37                                                                              4-methyl-2-thienyl                                                                           CH.sub.3                                                                          1 CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3                                                                         Cl 190.0                                                                               8                                                                              -                                   38                                                                              4-methyl-2-thienyl                                                                           CH.sub.3                                                                          1 CH.sub.3                                                                         CH.sub.3                                                                         H  Cl 231.2d                                                                             8 -                                   39                                                                              3-methyl-2-thienyl                                                                           H   1 1-pyridinyl                                                                            Cl 236.8d                                                                             8 -                                   40                                                                              3-methyl-2-thienyl                                                                           H   1 CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3                                                                         Cl 231.2d                                                                             8 -                                   41                                                                              5-methyl-2-furanyl                                                                           CH.sub.3                                                                          1 1-pyridinyl                                                                            Cl 214.2d                                                                             8 +                                   42                                                                              5-methyl-2-furanyl                                                                           CH.sub.3                                                                          1 CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3                                                                         Cl 190.7d                                                                             8 +                                   43                                                                              2,5-dimethyl-3-furanyl                                                                       CH.sub.3                                                                          1 1-pyridinyl                                                                            Cl 190.0d                                                                             8 +                                   44                                                                              2,5-methyl-3-furanyl                                                                         CH.sub.3                                                                          1 CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3                                                                         Cl 197.4d                                                                             8 +                                   45                                                                              4-methyl-2-thienyl                                                                           CH.sub.3                                                                          1 CH.sub.3                                                                         CH.sub.3                                                                         H  Cl 233.0d                                                                             8 -                                   46                                                                              3-methyl-2-thienyl                                                                           H   1 CH.sub.3                                                                         CH.sub.3                                                                         H  Cl 235.7                                                                              8 +                                   47                                                                              2-thienyl      c-C.sub.3 H.sub.5                                                                 1 1-pyridinyl                                                                            Cl 207.0d                                                                             8 -                                   48                                                                              2,4-dimethyl-5-thiazolyl                                                                     CH.sub.3                                                                          1 CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3                                                                         Cl 189.2d                                                                             1 +                                   49                                                                              2,4-dimethyl-5-thiazolyl                                                                     CH.sub.3                                                                          1 CH.sub.3                                                                         CH.sub.3                                                                         H  Cl 175.8d                                                                             1 +                                   50                                                                              5-methyl-1-phenyl-4-pyrazolyl                                                                CH.sub.3                                                                          1 1-pyridinyl                                                                            Cl 214.5d                                                                             1 +                                   51                                                                              5-methyl-2-thienyl                                                                           H   1 1-pyridinyl                                                                            Cl 228.8d                                                                             8 -                                   52                                                                              5-methyl-2-thienyl                                                                           H   1 CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3                                                                         Cl 221.5d                                                                             8 +                                   53                                                                              5-methyl-2-thienyl                                                                           H   1 CH.sub.3                                                                         CH.sub.3                                                                         H  Cl 225.2d                                                                             8 -                                   54                                                                              5-methyl-2-furanyl                                                                           H   1 1-pyridinyl                                                                            Cl 226.2d                                                                             8 +                                   55                                                                              5-methyl-2-furanyl                                                                           H   1 CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3                                                                         Cl 239.1d                                                                             8 -                                   56                                                                              5-methyl-2-furanyl                                                                           H   1 CH.sub.3                                                                         CH.sub.3                                                                         H  Cl 225.2d                                                                             8 -                                   57                                                                              3-benzothienyl CH.sub.3                                                                          1 1-pyridinyl                                                                            Cl 246.2d                                                                             8 +                                   58                                                                              3-benzothienyl CH.sub.3                                                                          1 CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3                                                                         Cl 236.0d                                                                             8 +                                   59                                                                              3-benzothienyl CH.sub.3                                                                          1 CH.sub.3                                                                         CH.sub.3                                                                         H  Cl 244.2d                                                                             8 -                                   60                                                                              2-pyrrolyl     H   1 1-pyridinyl                                                                            Cl 215-218d                                                                           1 +                                   61                                                                              2-pyrrolyl     H   1 CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3                                                                         Cl 224-226d                                                                           1 -                                   62                                                                              2-pyrrolyl     H   1 CH.sub.3                                                                         CH.sub.3                                                                         H  Cl 230-231d                                                                           1 -                                   63                                                                              1-methyl-2-pyrrolyl                                                                          H   1 1-pyridinyl                                                                            Cl 228-229d                                                                           1 -                                   64                                                                              1-methyl-2-pyrrolyl                                                                          H   1 CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3                                                                         Cl 239-241d                                                                           1 -                                   65                                                                              5-bromo-2-thienyl                                                                            CH.sub.3                                                                          1 CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3                                                                         Cl 203.8d                                                                             8 -                                   66                                                                              5-bromo-2-thienyl                                                                            CH.sub.3                                                                          1 CH.sub.3                                                                         CH.sub.3                                                                         H  Cl 198.6d                                                                             8 +                                   67                                                                              4-quinolinyl   H   1 1-pyridinyl                                                                            Cl 249.8d                                                                             1 -                                   68                                                                              4-quinolinyl   H   1 CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3                                                                         Cl 216.3d                                                                             1 +                                   69                                                                              1-methylindol-3-yl                                                                           H   1 1-pyridinyl                                                                            Cl 196.0d                                                                             1 +                                   70                                                                              1-methylindol-3-yl                                                                           H   1 CH.sub.3                                                                         CH.sub.3                                                                         H  Cl 253.0d                                                                             1 -                                   71                                                                              1-methylindol-3-yl                                                                           H   1 CH.sub.3                                                                         CH.sub.3                                                                         H  Cl 253.0d                                                                             1 -                                   72                                                                              2-pyrazinyl    CH.sub.3                                                                          1 1-pyridinyl                                                                            Cl 248.1d                                                                             2 +                                   73                                                                              2-pyrazinyl    CH.sub.3                                                                          1 CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3                                                                         Cl 249.5d                                                                             1 -                                   74                                                                              2-pyrazinyl    CH.sub.3                                                                          1 CH.sub.3                                                                         CH.sub.3                                                                         H  Cl 220.6d                                                                             1 -                                   75                                                                              2-thienyl      C.sub.2 H.sub.5                                                                   1 CH.sub.3                                                                         CH.sub.3                                                                         H  Cl 189.8                                                                              8 -                                   76                                                                              2-thienyl      C.sub.3 H.sub.7                                                                   1 CH.sub.3                                                                         CH.sub.3                                                                         H  Cl 166.4                                                                              8 +                                   77                                                                              5-methyl-1-phenyl-4-pyrazolyl                                                                CH.sub.3                                                                          1 CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3                                                                         Cl 150.7                                                                              1 +                                   78                                                                               3-methyl-2-pyrazinyl                                                                        CH.sub.3                                                                          1 1-pyridinyl                                                                            Cl 230.5d                                                                             1 +                                   79                                                                              3-methyl-2-pyrazinyl                                                                         CH.sub.3                                                                          1 CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3                                                                         Cl 217.6d                                                                             1 -                                   80                                                                              3-methyl-2-pyrazinyl                                                                         CH.sub.3                                                                          1 CH.sub.3                                                                         CH.sub.3                                                                         H  Cl 221.5d                                                                             1 -                                   81                                                                              2-(4-chlorophenyl)-4-                                                                        CH.sub.3                                                                          1 1-pyridinyl                                                                            Cl 238.5d                                                                             2 -                                     methyl-(2H)-1,2,3-triazolyl                                                 82                                                                              2-(4-chlorophenyl)-4-                                                                        CH.sub.3                                                                          1 CH.sub.3                                                                         CH.sub.3                                                                         CH.sub.3                                                                         Cl 230.0d                                                                             2 -                                     methyl-(2H)-1,2,3-triazolyl                                                 83                                                                              2-(4-chlorophenyl)-4-                                                                        CH.sub.3                                                                          1 CH.sub.3                                                                         CH.sub.3                                                                         H  Cl 257.9d                                                                             2 -                                     methyl-(2H)-1,2,3-triazolyl                                                 __________________________________________________________________________

                  TABLE I                                                         ______________________________________                                        H. Contortus                                                                                 % Clearance                                                    Compound No.     P.O     I.P                                                  ______________________________________                                        1                N.T.    N.T                                                  2                40.3    N.T                                                  3                27.0    N.T.                                                 4                0       N.T.                                                 5                0       N.T.                                                 6                N.T.    N.T.                                                 7                N.T.    N.T.                                                 ______________________________________                                    

                  TABLE II                                                        ______________________________________                                        Chemotherapeutic activity of Compound 1 in jirds                              ( M. unguiculatus) Against D. viteae and B. pahangi.                          Dose                 % Filarial Reduction of:                                 mg/kg/day    Admin.  Macrofil.   Microfil.                                    Cmpd.# x5        Route   BpL5  DvL5  4 days                                                                              56 days                            ______________________________________                                        1      100       SC      100   0     40    100                                ______________________________________                                         ##STR3##

X is a halogen atom or other active group, for example, an anhydride.

We claim:
 1. A method of killing parasitic worms in humans and valuablewarm-blooded domestic animal which comprises administering to humans orvaluable warm-blooded domestic animals in need, a therapeutic orprophylactic dosage of a pyridinyl quaternaryalkyl acylhydrazone,hydrate thereof, or pharmaceutically acceptable salt thereof of theformula IA:wherein X and Y, being the same or different, are selectedfrom hydrogen, hydroxy, C₁ -C₄ alkyl, C₁ -C₃ alkoxy, C₁ -C₃ alkylthio,halo or trifluoromethyl; with the proviso that only X or Y is hydroxy;wherein R₁ is hydrogen; C₁ -C₄ alkyl; cyclo(C₃ -C₆)alkyl optionallysubstituted with one, 2 or 3 C₁ -C₃ alkyl; phenyl optionally substitutedwith one, 2 or 3 C₁ -C₄ alkyl, halo, trifluoromethyl, or C₁ -C₃ alkoxy;phenyl(C₁ -C₃)alkyl optionally substituted with one, 2 or 3 C₁ -C₄alkyl, halo, trifluoromethyl, or C₁ -C₃ alkoxy, or1,3-dioxacyclohexan-5-yl; wherein n is 1-4; wherein m is 0 or 1; whereinR₂, R₃ and R₄ are taken together with the nitrogen to form pyridinyloptionally substituted with phenyl and/or one or two C₁ -C₄ alkyl or C₁-C₄ alkoxy; and X is a pharmaceutically acceptable anion.
 2. The methodof claim 1 wherein the compound of hydrate thereof is1-[2-oxo-2-[[[2-phenyl-1-(2-pyridinyl)ethylidene]hydrazino]ethyl]-pyridiniumchloride.
 3. The method according to claim 1 wherein X is a halogenatom, acetate or benzenesulfonate.
 4. The method according to claim 1wherein the parasitic worms are filarae.
 5. The method according toclaim 1 wherein the parasitic worms are Dirolilaria.
 6. A compound,hydrate thereof or pharmaceutical acceptable salt thereof of the formulaIA ##STR5## wherein X and Y, being the same or different, are selectedfrom hydrogen, hydroxy, C₁ -C₄ alkyl, C₁ -C₃ alkoxy, C₁ -C₃ alkylthio,halo or trifluoromethyl; with the proviso that only X or Y ishydroxy;wherein R₁ is hydrogen; C₁ -C₄ alkyl; cyclo(C₃ -C₆)alkyloptionally substituted with one, 2 or 3 C₁ -C₃ alkyl; phenyl optionallysubstituted with one, 2 or 3 C₁ -C₄ alkyl, halo, trifluoromethyl, or C₁-C₃ alkoxy; phenyl(C₁ -C₃)alkyl optionally substituted with one, 2 or 3C₁ -C₄ alkyl, halo, trifluoromethyl, or C₁ -C₃ alkoxy, or1,3-dioxacyclohexan-5-yl; wherein n is 1-4; wherein m is 0 or 1; whereinR₂, R₃ and R₄ are taken together with the nitrogen to form pyridinyloptionally substituted with phenyl and/or one or two C₁ -C₄ alkyl or C₁-C₄ alkoxy; and X is a pharmaceutically acceptable anion; other than1-[[[[1-(3-pyridinyl)ethylidene]hydrazino]carbonyl]methyl]pyridinumchloride; or1-[[[[1-(3-pyridinyl)ethylidene]hydrazino]carbonyl]propyl]pyridinumchloride.
 7. A compound according to claim 6 wherein the compound orhydrate thereof is1-[2-oxo-2-[[[2-phenyl-1-(2-pyridinyl)ethylidene]hydrazino]ethyl]-pyridiniumchloride.
 8. An anthelmintic composition for administration to animalscomprising a physiologically acceptable carrier and adjuvants, and atleast an effective anthelmintic amount of a pyridinyl quaternaryalkylacylhydrazone, hydrate thereof or pharmaceutically acceptable saltthereof of the formula IA ##STR6## wherein X and Y, being the same ordifferent, are selected from hydrogen, hydroxy, C₁ -C₄ alkyl, C₁ -C₃alkoxy, C₁ -C₃ alkylthio, halo or trifluoromethyl; with the proviso thatonly X or Y is hydroxy;wherein R₁ is hydrogen; C₁ -C₄ alkyl; cyclo(C₃-C₆)alkyl optionally substituted with one, 2 or 3 C₁ -C₃ alkyl; phenyloptionally substituted with one, 2 or 3 C₁ -C₄ alkyl, halo,trifluoromethyl, or C₁ -C₃ alkoxy; phenyl(C₁ -C₃)alkyl optionallysubstituted with one, 2 or 3 C₁ -C₄ alkyl, halo, trifluoromethyl, or C₁-C₃ alkoxy, or 1,3-dioxacyclohexan-5-yl; wherein n is 1-4; wherein m is0 or 1; wherein R₂, R₃ and R₄ are taken together with the nitrogen toform pyridinyl optionally substituted with phenyl and/or one or two C₁-C₄ alkyl or C₁ -C₄ alkoxy; and X is a pharmaceutically acceptableanion.